Protein kinases are the largest gene family in eucaryotic cells. They play essential regulating roles in multiple cellular processes, such as: cell proliferation, cell death, cell cycle process, differentiation, cell survival, etc. Protein Tyrosine Kinases (PTKs) are the most important category among the protein kinase family. PTKs play an important part in the signal transduction mechanism of normal cells. Their abnormal expression may cause many diseases, especially tumorigenesis, therefore, inhibiting overexpression of tyrosine kinases to restore physiological balance will become a new therapeutic regimen.
In the last 10 years, several innovative antitumor drugs based on signal pathway of tyrosine kinases have been successfully developed. Moreover, tyrosine kinases inhibitors (TKIs) has characteristics such as small molecules, orally effective and good tolerance, thus have been approved for treating multiple tumors, such as: lung cancer, breast cancer, renal carcinoma, pancreatic cancer, gastrointestinal cancer, chronic leukemia, etc.
More and more basic research and clinical studies demonstrate: tumor is a disease affected by multiple factors and signals, and its pathogenesis is very complicated (Giamas G., Man Y. L., Hirner H. Bischof J, Kramer K, Khan K, Ahmed S S, Stebbing J, Knippschild U. Kinases as targets in the treatment of solid tumors. Cell Signal 2010, 22(7), 984-1002). Multi-kinase inhibitors may inhibit or block several transducing pathways of cell growth signals, therefore, have already been the focus of tumor treatment and new medicine development.
c-Met is an important member of the tyrosine kinase family, which belongs to a receptor tyrosine kinases (RTK). c-Met was initially considered as an oncogenic fusion protein (TPR-MET), however, it has now been demonstrated that c-Met is a tyrosine kinases receptor coded by the proto-oncogene MET. It is the only high-affinity receptor of hepatocyte growth factor (HGF). During tumor onset and development, especially those with invasion and metastasis potential, HGF/c-Met signal pathway play an essential role. Tumor cells may stimulate adjacent fibroblasts to secrete HGF through releasing cytokines such as IL-1, FGF-2, and PDGF. Some tumor cells may show overexpression of both c-Met and HGF through autocrine route. Overexpression of c-Met may be observed in human hepatoma, cholangiocarcinoma, pancreatic cancer, lung cancer, thyroid cancer, pleural interstitialoma, etc. In case of metastatic tumor, HGF/c-Met signal pathway may influence tumor cell adhesion, promote degradation of extracellular matrix, induce angiogenesis, and facilitate cellular proliferation. Using the HGF/c-Met signal pathway as the target, it is relatively easy to realize simultaneous interference of multiple pathways. Once the HGF/c-Met signal pathway that shows abnormal activation and overexpression has been blocked in tumor cells, tumor cells will exert a series of changes including altered cell morphology, slower proliferation, lower tumorigenicity, and decreased invasion ability. (The MET oncogene drives a genetic programme linking cancer to haemostasis. Nature 2005, 434, 396-400; Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat. Rev. Drug Discov. 2008, 7, 504-516; Targeting receptor tyrosine kinase MET in cancer: small molecule inhibitors and clinical progress. J. Med. Chem. 2014, 57, 4427-4453.)
Vascular endothelial growth factor (VEGF) is the most effective and specific one among all pro-angiogenic factors which have been found up to now. VEGF may regulate process such as vascular geneisis, angiopoiesis and vascular migration, shows overexpression in many malignant tumors, and is closely related to growth, metastasis and prognosis. VEGFRs are tyrosine kinase transmembrane glycoproteins. VEGFR mainly include 3 receptors, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). VEGFR-2 is a specific glycoprotein, and has a relative molecular weight of 210000-230000. It mainly exists in vascular endothelial cells and hemopoietic stem cells. It may bind with VEGF-A, VEGF-C, VEGF-D, and VEGF-E, and mainly regulate the physiological reaction of VEGF in vascular endothelial cells, including permeability, proliferation and migration, therefore, it is a key signal transducer in physiological and pathologic angiogenic processes. VEGFR-2 exerts overexpression in case of ovarian cancer, thyroid cancer, melanoma and medulloblastoma, and supplies vast majorities of tumor tissues with nutrient by regulating tumor vascular system (including blood and lymph fluid). Additionally, the expression level of VEGFR-2 in tumors such as malignant intestinal cancer, lung cancer, and breast cancer is also significantly higher than that in non-tumor tissue. Some medicine may target at VEGFR signal response. Whether given alone or in combination with other chemotherapies, they are effective for patients with advanced malignant tumor. (An overview of small molecule inhibitors of VEGFR signaling. Nat. Rev. Clin. Oncol. 2009, 6, 569-579; Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Discovery 2011, 10, 417-427; Vascular Endothelial Growth Factor (VEGF) Receptors: Drugs and New Inhibitors. J. Med. Chem. 2012, 55, 10797-10822).
Axl kinase is a member of the TAM receptor tyrosine kinase family, binding with ligand Gas6 may activate Axl, thus initiate its downstream signal transducing pathway, and play a part in processes such as cell growth, migration, aggregation and apoptosis. A recent study shows, Axl kinase exerts overexpression or activation in many cancers, especially in cancer cells that develop resistance after chemotherapy and receptor tyrosine kinase inhibitor (TKI), the overexpression of Axl is very significant, and this is an important cause of developing resistance. Therefore, Axl kinase inhibitor is a new regimen to treat cancer. (Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors. Mol. Cancer Ther. 2014, 13, 2141-2148).
RET is a receptor tyrosine kinase, as a cell surface molecule, it can convert the signal for cell growth and differentiation. RET plays an important role in the development of nervous crest. Moreover, due to the rearrangement of cytogenetics, the carcinogenicity may be activated both in vivo and in vitro. The mutation caused by RET gene is related to multiple endocrine neoplasia, congenital megacolon, and medullary carcinoma of thyroid. The mutation with enhanced RET function may cause: medullary carcinoma of thyroid, onset of multiple endocrine neoplasia (types 2A and 2B), chromaffinoma, and parathyroid hyperplasia. RET rearrangement also occurs frequently in non-small cell lung cancer, and is closely related to onset and development of lung cancer. (Development of RET kinase inhibitors for targeted cancer therapy. Curr. Med. Chem. 2011, 18, 162-175).
Other pathogenic conditions related to protein kinases include psoriasis, liver cirrhosis, diabetes mellitus, angiogenesis, restenosis, ophthalmic diseases, rheumatoid arthritis and other inflammatory diseases, immunologically mediated disease, cardiovascular diseases such as arteriosclerosis, and many renal diseases.
Naphthyridine derivatives have broad-spectrum bioactivities, and important applications in the pharmaceutical field. In last years, many small molecules bearing naphthyridine scaffold have been widely used as protein kinase inhibitor in treating many diseases related to abnormal kinase activity, such as tumor, psoriasis, liver cirrhosis, diabetes mellitus, angiogenesis, ophthalmic diseases, rheumatoid arthritis and other inflammatory diseases, immunologically mediated disease, cardiovascular diseases such as arteriosclerosis, and many renal diseases. Wherein, 2,7-naphthyridines (WO2013033981, WO0192256, WO0242264), 1,5-naphthyridines (WO2006106046), 1,6-naphthyridines (WO2007060028, WO2010037249, WO2010088177), 2,6-naphthyridines (WO2008122614), fused heterocyclic naphthyridines (WO2009148887, WO2009148916), 2,7-naphthyridinones (WO2008109613, WO2009097287, WO2013033981), and 1,8-naphthyridinones (WO2010002779) are also used as protein kinase inhibitor.

1,6-naphthyridines-1(2H)-ketones are important naphthyridine compounds, with a molecular formula of C8H6N2O, and a molecular weight of 146.1, and they have the chemical structure as shown above.

General Formula of Compounds Revealed by WO2013097753
1,6-naphthyridines-1(2H)-ketones have been rarely reported to be used as therapeutic protein kinase inhibitor, and only the patent WO2013097753 revealed a category of 1,6-naphthyridines-1(2H)-ketones as c-Met kinase inhibitor. This patent focuses on a series of compounds whose block A is replaced by quinazoline. However, analyzing the structural characteristics of some commercial kinase inhibitors shows, when the block A is a quinoline ring, the pharmaceutical potential of the compounds is higher. Therefore, this invention attempts to develop naphthyridines with more structural types, and better kinase inhibiting activity and efficacy against diseases.